The retina is exposed to light intensities that vary over nine orders of magnitude, from a cloudy night in a forest to a sunny day on a snowy mountainside, and to images of varying contrast and frequency. To optimize vision over this entire range, the response properties of the retina change as a function of the stimuli at both the cellular and network level, a process termed adaptation. The long-term goal of the proposed research is to explain the molecular basis for regulation of the light response in retinal ON-bipolar cells. These cells mediate the transmission of light responses between photoreceptors and ganglion cells and are key sites of adaptation. Rod bipolar cells receive light-driven synaptic input from rod photoreceptors and drive retinal output via synapses onto AII amacrine cells. While dark-adapted rod bipolar cells can transmit single photon responses in starlight, they are also able to transmit contrast changes in moderate background light. The mechanisms which optimize rod bipolar cell function under different lighting conditions remain unknown. Our recent work suggests that a novel mGlu5-based pathway operating in parallel to the primary light-response pathway may modulate the ON-bipolar cell responses. Further, we have identified a potassium channel, Kv11.1, that appears to regulate dark adaptation, and may be regulated by PKC?, which is abundantly expressed in rod bipolar cells. In the dark, photoreceptors release glutamate onto dendrites of ON-bipolar cells, and decrease glutamate release in response to light stimuli. The light response of ON-bipolar cells is mediated by a unique, sign- inverting pathway initiated by mGlu6, a G protein-coupled receptor in the ON-bipolar cell dendrites. In the dark, tonic activation of the mGlu6 pathway maintains the TRPM1 cation channel in a closed state. In response to light stimuli, mGlu6 is inactivated, allowing TRPM1 channels to open and depolarize the cell. The mGlu6- TRPM1 pathway is conserved in all vertebrates, and mutations in mGlu6 and TRPM1 cause congenital stationary night blindness (CSNB) in humans and mouse models. Despite its central importance in vision, the molecular mechanisms by which the primary excitatory pathway is modulated under different conditions remain unknown. Based on analogy with other systems, and our Preliminary Studies, we hypothesize that mGlu5 receptors, Kv11.1 channels and PKC? modulate the output of the mGlu6-TRPM1 pathway.